Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996), and all references cited therein. According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases, including, for example, nephropathy, neuropathy, hypertension, cerebrovascular disease, and coronary heart disease. Additionally, uncontrolled hyperglycemia is associated with an increased risk of blindness due to retinopathy. Therefore, control of glucose homeostasis is an important approach for the treatment of diabetes.
There are two major forms of diabetes: Type 1 diabetes (formerly referred to as insulin-dependent diabetes mellitus or IDDM); and Type 2 diabetes (formerly referred to as noninsulin dependent diabetes mellitus or NIDDM). Type 1 diabetes is the result of an absolute deficiency of insulin, the hormone which regulates glucose utilization. This insulin deficiency is usually characterized by β-cell destruction within the Islets of Langerhans in the pancreas and absolute insulin deficiency. Type 2 diabetes is a disease characterized by insulin resistance accompanied by relative, rather than absolute, insulin deficiency. Type 2 diabetes can range from predominant insulin resistance with relative insulin deficiency to predominant insulin deficiency with some insulin resistance. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin-resistant individuals the body secretes abnormally high amounts of insulin to compensate for this defect. When inadequate amounts of insulin are present to compensate for insulin resistance and adequately control glucose, a state of impaired glucose tolerance develops. In a significant number of individuals, insulin secretion declines further and the plasma glucose level rises, resulting in the clinical state of diabetes.
The majority of Type 2 diabetic patients are treated either with hypoglycemic agents, which act by stimulating release of insulin from beta cells, or with agents that enhance the tissue sensitivity of the patients to insulin, or with insulin. Sulfonylureas are examples of agents that stimulate release of insulin from beta cells. Among the agents applied to enhance tissue sensitivity to insulin, metformin is a representative example. Even though sulfonylureas are widely used in the treatment of type II diabetes, this therapy is, in most instances, not satisfactory. In a large number of type II diabetic patients sulfonylureas do not suffice to normalize blood sugar levels and the patients are, therefore, at high risk for acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are, thus, gradually forced into insulin treatment. This shift of patients from oral hypoglycemic agents to insulin therapy is usually ascribed to exhaustion of the pancreatic β cells in type II diabetic patients. The guidelines for diagnosis for Type 2 diabetes, impaired glucose tolerance, and gestational diabetes have been outlined by the American Diabetes Association (see, e.g., The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus, Diabetes Care, (1999) Vol 2 (Suppl 1): S5-19), which is incorporated by reference in its entirety herein.
In addition to glucose transport, insulin is intimately involved in adipogenesis, a process which involves proliferation of preadipocytes (pre-fat cells) and differentiation of preadipocytes into adipocytes (fat cells) with accumulation of fat in adipocytes. As a result of its adipogenic effect, insulin has the undesirable effect of promoting obesity in patients with type 2 diabetes. (See, Moller, D. E. (2001) Nature 414:821-827.) Unfortunately, other anti-diabetic drugs, which are currently being used to stimulate glucose transport in patients with type 2, diabetes also possess adipogenic activity.
Syndrome X, also called metabolic syndrome, is a cluster of health conditions or disorders of the metabolism. It is marked by abdominal obesity, elevated levels of triglycerides, low levels of HDL (“good”) cholesterol, high blood pressure, and/or high blood sugar levels. Recent research shows the metabolic syndrome has become increasingly common in the United States. Up to 25% (or about 50 million) of adults between the ages of 20 and 79 have at least three of these symptoms, with the prevalence approaching 50% in the elderly. It can affect anyone at any age, but it is most frequently seen in those who are significantly overweight (with most of their excess fat in the abdominal area) and inactive. When these conditions occur together, they may significantly increase the risk for developing type II diabetes and heart disease. Syndrome X can be considered as a major risk factor or a prelude for type II diabetes. Each of these disorders in Syndrome X is by itself a risk factor for other diseases. In combination, though, these disorders dramatically boost an individual's chances of developing potentially life-threatening illnesses.
Syndrome X is closely associated with a generalized metabolic disorder called insulin resistance, in which the body cannot use insulin efficiently. This is why Syndrome X is also called the insulin resistance syndrome. One group of people with insulin resistance are those with diabetes who have a defect in insulin action and cannot maintain a proper level of glucose in their blood. Another group includes people, mainly those with high blood pressure, who are nondiabetic and insulin resistant but who compensate the defect by secreting large amounts of insulin. This condition is known as hyperinsulinemia. A third group is heart attack survivors who, unlike hypertensives, have hyperinsulinemia without having abnormal glucose levels. Syndrome X is described in the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, ATP III), which is incorporated by reference.
Accordingly, there remains a need in the art for anti-diabetic drugs and/or anti-adipogenic drugs to treat conditions such as diabetes, obesity, and/or Syndrome X.